Clinical phenotype and outcome of hypertrophic cardiomyopathy associated with thin-filament gene mutations

J Am Coll Cardiol. 2014 Dec 23;64(24):2589-2600. doi: 10.1016/j.jacc.2014.09.059.

Abstract

Background: Mild hypertrophy but increased arrhythmic risk characterizes the stereotypic phenotype proposed for hypertrophic cardiomyopathy (HCM) caused by thin-filament mutations. However, whether such clinical profile is different from more prevalent thick-filament-associated disease is unresolved.

Objectives: This study aimed to assess clinical features and outcomes in a large cohort of patients with HCM associated with thin-filament mutations compared with thick-filament HCM.

Methods: Adult HCM patients (age >18 years), 80 with thin-filament and 150 with thick-filament mutations, were followed for an average of 4.5 years.

Results: Compared with thick-filament HCM, patients with thin-filament mutations showed: 1) milder and atypically distributed left ventricular (LV) hypertrophy (maximal wall thickness 18 ± 5 mm vs. 24 ± 6 mm; p < 0.001) and less prevalent outflow tract obstruction (19% vs. 34%; p = 0.015); 2) higher rate of progression to New York Heart Association functional class III or IV (15% vs. 5%; p = 0.013); 3) higher prevalence of systolic dysfunction or restrictive LV filling at last evaluation (20% vs. 9%; p = 0.038); 4) 2.4-fold increase in prevalence of triphasic LV filling pattern (26% vs. 11%; p = 0.002); and 5) similar rates of malignant ventricular arrhythmias and sudden cardiac death (p = 0.593).

Conclusions: In adult HCM patients, thin-filament mutations are associated with increased likelihood of advanced LV dysfunction and heart failure compared with thick-filament disease, whereas arrhythmic risk in both subsets is comparable. Triphasic LV filling is particularly common in thin-filament HCM, reflecting profound diastolic dysfunction.

Keywords: diastolic function; end-stage; genotype to phenotype correlation; triphasic filling; troponin.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actin Cytoskeleton / genetics
  • Actins / genetics*
  • Adult
  • Cardiomyopathy, Hypertrophic* / complications
  • Cardiomyopathy, Hypertrophic* / diagnosis
  • Cardiomyopathy, Hypertrophic* / genetics
  • Cardiomyopathy, Hypertrophic* / physiopathology
  • Death, Sudden, Cardiac / etiology
  • Disease Progression
  • Female
  • Follow-Up Studies
  • Genetic Predisposition to Disease
  • Heart Function Tests
  • Humans
  • Italien
  • MAP Kinase Kinase Kinases / genetics*
  • Male
  • Middle Aged
  • Mutation
  • Patient Outcome Assessment
  • Protein Serine-Threonine Kinases
  • Severity of Illness Index
  • Troponin T / genetics*
  • Ventricular Dysfunction, Left / etiology
  • Ventricular Dysfunction, Left / genetics
  • Ventricular Fibrillation / etiology
  • Ventricular Fibrillation / genetics
  • Ventricular Outflow Obstruction / etiology
  • Ventricular Outflow Obstruction / genetics

Substances

  • ACTC1 protein, human
  • Actins
  • TNNT2 protein, human
  • Troponin T
  • Protein Serine-Threonine Kinases
  • TNNI3K protein, human
  • MAP Kinase Kinase Kinases